Regulation of IL-4 lymphokine gene expression and cellular proliferation in murine T helper type II cells.

Abstract

Activation of T cells results in the production of lymphokines and cellular proliferation. Protein kinase C (PKC) plays a key role in this process. It has been shown that this enzyme is essential to elicit a response to Con A or specific antigen in CD4+ T helper type 1 (Th 1) cells that secrete IL-2. We have now explored the signal transduction pathway that leads to transcription of the IL-4 gene and proliferation in murine CD4+ T helper type 2 (Th 2) cells. Surprisingly, we have found in two independently derived Th 2 clones that neither cellular proliferation nor IL-4 lymphokine production is affected by blocking or depletion of PKC. This differential mechanism of signal transmission leading to cellular activation implies a new distinction between murine Th 1 and Th 2 cells.

Differences between T helper cell type I (Th1) and Th2 cell lines in signalling pathways for induction of contact‐dependent T cell help

“…Forskolin and dbcAMP blocked IL 2 production but did not affect production of IL 3 or ITCH in T h l or Th2 cells, or IL 4 in Th2 cells. This selective effect of CAMP agonists on 1L 2 expression may be accounted for by direct inhibition of IL 2 gene transcription [18,191, since cAMP agonists inhibit transcription of the IL 2 gene, but not the IL 4 gene, in a promoter-specific manner [34]. This is consistent with recent observations by other laboratories that glucocorticoids [35] or prostaglandin Ez [36] inhibits IL 2 production but not IL 4 production in someTh clones which secrete both lymphokines.…”

“…In fact, neither elevation of intracellular calcium concentration nor phosphatidyl inosi-to1 (PI) turnover was detected after receptor-mediated stimulation of Th2 cells, whereas both were detected in Thl cells [17]. In addition, it was shown that Th2 cells can respond to antigenic stimulation by lymphokine production and proliferation in the absence of functional PKC and are less dependent on PKC activation thanTh1 cells [18].These observations suggest that second messengers other than PKC and Ca2+/calmodulin are used for a major signal transduction pathway linked to TcR/CD3 in Th2 cells. In addition, Th2 cells are less sensitive to cAMP agonists and cyclosporine A than Thl cells [17, 191. In the present study, we examined inducible Tcell contact help activity (ITCH) in addition to production of lymphokines inThl and Th2 cells, since both are essential functions for induction of small resting B cell proliferation, and demonstrated additional differences between Thl and Th2 cell lines in the signalling pathways leading from the TcR to the induction of helper functions for small resting B cell proliferation.…”

Transcription of the interleukin 4 gene is regulated by multiple promoter elements.

“…In fact, certain Th2 clones, including D10, do not flux calcium in response to TCR stimulation (28,29). These clones, however, can still produce significant amounts oflL-4 upon TCR engagement (30). Our data would support at least some divergence between calcium-dependent and -independent pathways leading to IL-4 gene transcription.…”

Development of human Th1 and Th2 cytokine responses: The cytokine production profile of T cells is dictated by the primary in vitro stimulus

“…23: 1-5 The activity of PKC in established murineTh2 clones seems less important than in Thl clones; Th2 clones did not produce elevated calcium and inositol phosphate levels after T cell receptor triggering in contrast toThl cells [ 141. In other studies on murineTh2 cells, PKC depletion did not affect IL-4 production [15,161,although PKC stimulation was shown to have dual effects on IL-4 mRNA production, i.e. a positive effect early (3 h) during stimulation, but a negative effect after 24 h [15].…”

“…In other studies on murineTh2 cells, PKC depletion did not affect IL-4 production [15,161,although PKC stimulation was shown to have dual effects on IL-4 mRNA production, i.e. a positive effect early (3 h) during stimulation, but a negative effect after 24 h [15]. Relatively high amounts of the PKC activator PBuz could even inhibit IL-4 production by Th2 clones [16].…”